Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDA) has the worst five-year survival rate of any major cancer. The lethality of PDA is largely due to a lack of effective treatment options. Several barriers in PDA treatment are conferred by the presence of immunosuppressive myeloid cells, which are highly represented in these tumors. This immune suppression, driven largely by myeloid cells, renders PDA refractory to immunotherapy which has proven effective in other solid tumors. Consequently, the elimination or reprogramming of these myeloid cells offers potential avenues to provide a much-needed breakthrough for the treatment of patients with PDA. The working hypothesis of this proposal is that interruption of the metabolic mechanisms driving immune suppression will sensitize pancreatic cancer to immunotherapy. This will be examined in three parts. First, core metabolic pathways in myeloid cells programmed by PDA cells will be identified and the requirement of these programs for functionality will be tested (Aim 1). Next, the metabolic mechanisms by which these myeloid cells mediate immune suppression will be investigated using human and murine co-culture, organoid, and in vivo systems (Aim 2). Finally, these interactions will be targeted in tumor models coupled with checkpoint inhibitors to determine the translational value of these approaches (Aim 3). The mentored phase of this career development award will be overseen by Drs. Costas Lyssiotis and Weiping Zou at the University of Michigan Medical School. In addition, Drs. Gabriel Nunez, Marina Pasca di Magliano, and Charles Burant will serve as a postdoctoral advisory committee. Together, the mentorship team has set forth a career development plan focused on research, collaboration, grantsmanship, presentation, mentorship, and the acquisition of management skills necessary to run an independent research program. This will be carried out utilizing the exceptional resources available at the University of Michigan.